This invention relates to a methods for the treatment or prophylaxis of post-traumatic stress disorder (PTSD) using topiramate and related sulfamate derivatives and analogues, and the pharmacologically acceptable acid addition salts thereof, alone or in association with a pharmaceutically acceptable carrier.
Chronic post-traumatic stress disorder (PTSD) is a difficult to treat condition. To date, the U.S. Food and Drug Administration has approved only one medication, sertraline, for the treatment of PTSD, and has limited the indication to women. Hypotheses on the etiology of PTSD have suggested that after exposure to traumatic events, limbic nuclei may become kindled or sensitized. Consequently, drugs known to have anti-kindling or anticonvulsant effects have been assessed as treatments for PTSD. (See Post RM et al., xe2x80x9cCocaine, kindling, and psychosis,xe2x80x9d Am J Psychiatry 133:627-634 (1976); Post RM et al., xe2x80x9cConditioning and sensitisation in the longitudinal course of affective illness,xe2x80x9d Br J Psychiatry 149:191-201 (1986); and Post RM et al., xe2x80x9cKindling versus quenching. Implications for the evolution and treatment of posttraumatic stress disorder,xe2x80x9d Ann N Y Acad Sci 821:285-295 (1997)). For example, carbamazepine may reduce reexperiencing and arousal symptoms, whereas valproate may reduce avoidance/numbing and arousal symptoms but not re-experiencing symptoms. (See Keck PE et al., xe2x80x9cValproate and carbamazepine in the treatment of panic and posttraumatic stress disorders, withdrawal states and behavioural dyscontrol syndromes,xe2x80x9d J Clin Physchopharmacol 12(suppl 1):36-41 (1992).)
The generic class of compounds of the following formula I: 
are structurally similar antiepileptic compounds that are highly effective anticonvulsants in animal tests (Maryanoff, B. E. et al., Med. Chem. 30:880-887 (1987); Maryanoff, B. E. et al., Bioorganic and Medicinal Chemistry Letters 3:2653-2656 (1993), McComsey, D. F. et al., J. Org. Chem. 1995). These compounds are covered by three U.S. Pat. Nos.: 4,5.13,006, 5,384,327 and 5,498,629. One of these compounds 2,3:4,5-bis-O-(1-methylethylidene)-xcex2-D-fructopyranose sulfamate known as topiramate has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures (E. Faught et. al., Epilepsia 36 (S4) 33, 1995; S. K. Sachdeo et al., Epilepsia 36 (S4) 33, 1995), and is currently marketed for the treatment of simple and complex partial seizure epilepsy with or without secondary generalized seizures in Great Britain, Finland, the United States, Sweden and elsewhere, and applications for regulatory approval are presently pending or have been approved in over 50 countries throughout the world.
Compounds of Formula I were initially found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice (Shank, R. P. et al., Epilepsia 35 450-460, 1994). Subsequent studies revealed that Compounds of Formula I were also highly effective in the MES test in rats. More recently topiramate was found to effectively block seizures in several rodent models of epilepsy (J. Nakamura et al., Eur. J. Pharmacol. 254 83-89, 1994), and in an animal model of kindled epilepsy (A. Wauquier et al., Epilepsy Res. 24, 73-77, 1996).
More recently, topiramate has been shown to have efficacy in the treatment of a broad range of seizure types in adults and children. (Faught E., xe2x80x9cEfficacy of topiramate as adjunctive therapy in refractory partial seizures: United States trial experience,xe2x80x9d Epilepsia 38(suppl 1):24-27 (1997); Ben-Menachem E., xe2x80x9cClinical efficacy of topiramate as add-on therapy in refractory partial epilepsy: The European experience,xe2x80x9d Epilepsia 38(suppl 1):28-30 (1997); Reife R A et al., xe2x80x9cTopiramate as adjunctive therapy in refractory partial epilepsy: Pooled analysis of data from five double-blind, placebo-controlled trials,xe2x80x9d Epilepsia 38(suppl 1):31-33 (1997); Rosenfeld W E et al., xe2x80x9cLong-term experience with topiramate as adjunctive therapy and as monotherapy in patients with partial onset seizures: Retrospective study of open-label treatment,xe2x80x9d Epilepsia 38(suppl 1):34-36 (1997); Biton V., xe2x80x9cPreliminary open-label experience with topiramate in primary generalized seizures,xe2x80x9d Epilepsia 38(suppl 1):42-44 (1997); Glauser T A, xe2x80x9cTopiramate use in pediatric patients,xe2x80x9d Can J Neurol Sci 25:8-12 (1998); and Elterman R D et al., xe2x80x9cA double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topirarnate Y P Study Group.,xe2x80x9d Neurology 52:1338-1344 (1999)). The drug has an usually broad spectrum of pharmacological properties, with several proposed mechanisms of action. In addition to carbonic anhydrase inhibition, topiramate induces state-dependent blockade of voltage-gated Na+ channels, enhances GABAergic activity at GABAA receptors, blocks glutamate inhibition at kainate/AMPA receptors, and promotes protein phosphorylation of neuronal conductance channels. Topiramate thus combines several pharmacological properties of carbamazepine and valproate. In addition, U.S. Pat. No. 5,753,693 discloses that topiramate, and the sulfamate derivatives of formula I (above) are useful for the treatment of manic-depressive bipolar disorder (MDBD).
Recent preclinical studies on topiramate have revealed previously unrecognized pharnacological properties, which suggest that topiramate should be effective in treating post traumatic stress disorder (PTSD).
In accordance with the present invention, it has been found that topiramate and related sulfamate compounds of the following formula I: 
wherein X is O or CH2, and R1, R2, R3, R4 and R5 are as defined hereinafter, and the pharmacologically acceptable acid addition salts thereof, alone or in association with a pharmaceutically acceptable carrier, are useful in treating post traumatic stress disorder (PTSD). The compounds of the invention may also be used prophylactically to lessen the frequency and/or intensity of PTSD symptoms following a traumatic event.
This and other aspects of the invention will become apparent from the description of the invention which follows below.